Dong Weilai, Jin Sheng Chih, Allocco August, Zeng Xue, Sheth Amar H, Panchagnula Shreyas, Castonguay Annie, Lorenzo Louis-Étienne, Islam Barira, Brindle Geneviève, Bachand Karine, Hu Jamie, Sularz Agata, Gaillard Jonathan, Choi Jungmin, Dunbar Ashley, Nelson-Williams Carol, Kiziltug Emre, Furey Charuta Gavankar, Conine Sierra, Duy Phan Q, Kundishora Adam J, Loring Erin, Li Boyang, Lu Qiongshi, Zhou Geyu, Liu Wei, Li Xinyue, Sierant Michael C, Mane Shrikant, Castaldi Christopher, López-Giráldez Francesc, Knight James R, Sekula Raymond F, Simard J Marc, Eskandar Emad N, Gottschalk Christopher, Moliterno Jennifer, Günel Murat, Gerrard Jason L, Dib-Hajj Sulayman, Waxman Stephen G, Barker Fred G, Alper Seth L, Chahine Mohamed, Haider Shozeb, De Koninck Yves, Lifton Richard P, Kahle Kristopher T
Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
iScience. 2020 Sep 11;23(10):101552. doi: 10.1016/j.isci.2020.101552. eCollection 2020 Oct 23.
Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated mutation (p.Cys188Trp) in the GABA receptor Cl channel γ-1 subunit () exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na and Ca channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca channel Ca3.2 (). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.
三叉神经痛（TN）是一种常见的、使人衰弱的神经性面部疼痛综合征，通常对治疗有抵抗性。TN病例的家族聚集表明遗传因素在疾病发病机制中起作用。然而，迄今为止尚未进行关于TN的无偏倚、大规模基因组研究。对290例全外显子测序的TN先证者进行分析，包括20个多位点家系和70个亲子三联体，结果显示病例中GABA受体结合基因存在罕见的有害变异富集。在GABA受体氯离子通道γ-1亚基（）中携带TN相关突变（p.Cys188Trp）的工程小鼠表现出三叉神经机械性异常性疼痛和面部疼痛行为。其他TN先证者在钠通道和钙通道中存在罕见的有害变异，包括电压门控钙通道Ca3.2（）的α-1H亚基中有显著的变异负荷。这些结果为TN提供了外显子水平的见解，并表明GABA信号传导的遗传编码损伤和神经元离子转运在TN发病机制中起作用。
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